ADALAT LA 30 MG PROLONGED-RELEASE TABLETS

Main information

  • Trade name:
  • ADALAT LA 30 MG PROLONGED-RELEASE TABLETS
  • Dosage:
  • 30 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ADALAT LA 30 MG PROLONGED-RELEASE TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/012/005B
  • Authorization date:
  • 14-12-2001
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AdalatLA30mgProlonged-releaseTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains30mgofnifedipine.

Excipients:Sodium

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolonged-releasetablet

ProductimportedfromTheNetherlandsandGreece:

Pink,lacqueredtabletsprinted‘Adalat30’inblackononeside,plainontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Adalatisindicatedforthetreatmentofmildtomoderatehypertensionandforthemanagementofchronicstableangina

pectoriseitherasmonotherapyorincombinationwithabeta-blocker.

4.2Posologyandmethodofadministration

Fororaladministration,thetabletsshouldbeswallowedwholewithaglassofwater.Thetabletsshouldbetakenat

approximately24-hourintervals,i.e.atthesametimeeachday,preferablyduringthemorning.AdalatLAtabletsmust

beswallowedwhole;undernocircumstancesshouldtheybebitten,chewedorbrokenup.

Inhypertension,therecommendedinitialdoseisone20mgtabletonce-daily.Ifnecessary,thedosagecanbeincreased

accordingtoindividualrequirementsuptoamaximumof90mgonce-daily.

Forthemanagementofanginapectoris,therecommendedinitialdoseisone30mgtabletonce-daily.Thedosagecan

beincreasedaccordingtoindividualrequirementsuptoamaximumof90mgonce-daily.

PatientsinwhomhypertensionoranginalsymptomsarecontrolledonAdalatcapsulesorAdalatretardmaybe

switchedsafelytoAdalatLA.Prophylacticanti-anginalefficacyismaintainedwhenpatientsareswitchedfromother

calciumantagonistssuchasdiltiazemorverapamiltoAdalatLA.Patientsswitchedfromothercalciumantagonists

shouldinitiatetherapyattherecommendedinitialdoseof30mgAdalatLAonce-daily.Subsequenttitrationtoahigher

dosemaybeinitiatedaswarrantedclinically.

Thepharmacokineticsofnifedipinearealteredintheelderlysothatlowermaintenancedosesofnifedipinemaybe

requiredcomparedtoyoungerpatients.

Patientswithrenalimpairmentshouldnotrequireadjustmentofdosage.

Treatmentmaybecontinuedindefinitely.

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AdalatLAshouldnotbetakenwithgrapefruitjuice(seeSection4.5).

4.3Contraindications

AdalatLAshouldnotbeadministeredtopatientswithknownhypersensitivitytonifedipineorotherdihydropyridines

becauseofthetheoreticalriskofcross-reactivity.

AdalatLAshouldnotbeadministeredtowomencapableofchild-bearingortonursingmothers.

AdalatLAshouldnotbeusedincardiogenicshock,clinicallysignificantaorticstenosis,unstableanginapectoris,or

duringorwithinonemonthofamyocardialinfarction.

AdalatLAshouldnotbeusedforthetreatmentofacuteattacksofangina.

ThesafetyofAdalatLAinmalignanthypertensionhasnotbeenestablished.

AdalatLAshouldnotbeusedforsecondarypreventionofmyocardialinfarction.

Owingtothedurationofactionoftheformulation,AdalatLAshouldnotbeadministeredtopatientswithhepatic

impairment.

AdalatLAshouldnotbeadministeredtopatientswithahistoryofgastro-intestinalobstruction,oesophageal

obstruction,oranydegreeofdecreasedlumendiameterofthegastro-intestinaltract.

AdalatLAiscontra-indicatedinpatientswithinflammatoryboweldiseaseorCrohn’sdisease.

AdalatLAshouldnotbeadministeredconcomitantlywithrifampicinsinceeffectiveplasmalevelsofnifedipinemay

notbeachievedowingtoenzymeinduction(seeSection4.5).

4.4Specialwarningsandprecautionsforuse

AdalatLAtabletsmustbeswallowedwhole;undernocircumstancesshouldtheybebitten,chewedorbrokenup.

TheoutermembraneoftheAdalatLAtabletisnotdigestedand,therefore,whatappearstobethecompletetabletmay

beseeninthetoiletorassociatedwiththepatient’sstools.

Cautionshouldbeexercisedinpatientswithhypotensionasthereisariskoffurtherreductioninbloodpressure.

AdalatLAshouldbeusedwithcautioninpatientswhosecardiacreserveispoor.Deteriorationofheartfailurehas

occasionallybeenobservedwithnifedipine.

Ischaemicpainhasbeenreportedinasmallproportionofpatientsfollowingtheintroductionofnifedipinetherapy.

Althougha“steal”effecthasnotbeendemonstrated,patientsexperiencingthiseffectshoulddiscontinuenifedipine

therapy.

DiabeticpatientstakingAdalatLAmayrequireadjustmentoftheircontrol.

Indialysispatientswithmalignanthypertensionandhypovolaemia,amarkeddecreaseinbloodpressurecanoccur.

Whilstnifedipineiscontraindicatedinpregnancy,particularcaremustbeexercisedwhenadministeringnifedipinein

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Co-administrationofnifedipinewitherythromycin,ketoconazole,itraconazole,fluconazole,fluoxetine,indinavir,

nelfinavir,ritonavirandsaquinavir,maytheoreticallyresultinanincreaseinnifedipineplasmaconcentrations.Upon

co-administrationwithanyofthesecytochromeP4503A4inhibitors,bloodpressureshouldbemonitoredand,if

necessary,areductioninthenifedipinedoseconsidered(seeSection4.5).

AstheoutermembraneoftheAdalatLAtabletisnotdigested,careshouldbeexercisedasobstructivesymptomsmay

occur,particularlyinpatientswithpre-existingseveregastrointestinalnarrowing.

AdalatLAmustnotbeadministeredtopatientswithKockpouch(ileostomyafterproctocolectomy).

Afalsepositiveeffectmaybeexperiencedwhenperformingabariumcontrastx-ray.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

KnownInteractions

Aswithotherdihydropyridines,nifedipineshouldnotbetakenwithgrapefruitjuiceaselevatedplasmaconcentrations

occur,duetoadecreasedfirstmetabolism.Asaconsequence,thebloodpressureloweringeffectofnifedipinemaybe

increased.Afterregularintakeofgrapefruitjuice,thiseffectmaylastforatleastthreedaysafterthelastingestionof

grapefruitjuice(seesection4.2).

TheantihypertensiveeffectofAdalatLAmaybepotentiatedbysimultaneousadministrationofcimetidine.

Whenusedincombinationwithnifedipine,serumquinidinelevelshavebeenshowntobesuppressedregardlessof

dosageofquinidine.Therefore,monitoringofquinidineplasmalevelsandifnecessaryadjustmentofthequinidine

dosagearerecommended.Thepharmacokineticsofnifedipinemayalsobealteredwhenusedincombinationwith

quinidine.Itisthereforerecommendedtomonitorbloodpressure,andifnecessaryreducethenifedipinedosage.

Thesimultaneousadministrationofnifedipineanddigoxinmayleadtoreduceddigoxinclearanceand,hence,an

increaseintheplasmadigoxinlevel.Plasmadigoxinlevelsshouldbemonitoredand,ifnecessary,thedigoxindose

reduced.

PhenytoininducesthecytochromeP4503A4system.Uponco-administrationwithphenytoin,thebioavailabilityof

nifedipineisreducedandthusitsefficacyweakended.Whenbothdrugsareconcomitantlyadministered,theclinical

responsetonifedipineshouldbemonitoredand,ifnecessary,anincreaseofthenifedipinedoseconsidered.Ifthedose

ofnifedipineisincreasedduringco-administrationofbothdrugs,areductionofthenifedipinedoseshouldbe

consideredwhenthetreatmentwithphenytoinisdiscontinued.

Diltiazemdecreasestheclearanceofnifedipineand,hence,increasesplasmanifedipinelevels.Therefore,caution

shouldbetakenwhenbothdrugsareusedincombinationandareductionofthenifedipinedosemaybenecessary.

Nifedipinemayincreasethespectrophotometricvaluesofurinaryvanillylmandelicacidfalsely.However,HPLC

measurementsareunaffected.

AdalatLAshouldnotbeadministeredconcomitantlywithrifampicinsinceeffectiveplasmalevelsofnifedipinemay

notbeachievedowingtoenzymeinduction(seesection4.3).

Simultaneousadministrationofcisaprideandnifedipineorquinupristin/dalfopristinandnifedipinemayleadto

increasedplasmaconcentrationsofnifedipine.Consequently,thebloodpressureshouldbemonitoredand,ifnecessary,

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TheoreticalInteractions

NifedipineismetabolisedviathecytochromeP4503A4systemand,therefore,therearetheoreticalinteractionsfor

drugswhochareknowntoinhibitthisenzymesystem(e.g.erythromycin,ketoconazole,itraconazole,fluconazole,

fluoxetine,indinavir,nelfinavir,ritonavir,amprenavirandsaquinavir).Althoughnoformalinvivointeractionstudies

havebeenperformedwiththesedrugs,co-administrationcanbeexpectedtoleadtoanincreaseinplasma

concentrationsofnifedipine.Bloodpressureshouldthereforebemonitoredand,ifnecessary,areductioninthe

nifedipinedoseconsidered(seesection4.4).

TacrolimushasbeenshowntobemetabolisedviathecytochromeP4503A4mediatedmetabolismofotherdrugs.

Thereforeanincreaseinnifedipineplasmaconcentrationsuponco-administrationofbothdrugscannotbeexcluded.

Whennefazodoneisgiventogetherwithnifedipine,thebloodpressureshouldbemonitoredand,ifnecessary,a

reductioninthenifedipinedoseconsidered.

Althoughnoformalinteractionstudieshavebeenperformedbetweennifedipineandcarbamazepine,phenobarbitoneor

valproicacid,thesedrugshavebeenshowntoaltertheplasmaconcentrationsandhenceandalterationinefficacy

cannotbeexcluded.

Drugsshownnottointeractwithnifedipine:

Thefollowingdrugshavebeenshowntohavenoeffectonthepharmacokineticsofnifedipinewhenadministered,

doxazosin,irbesartan,omeprazole,orlistat,pantoprazole,ranitidine,rosiglitazone,talinololandtriamterene

hydrochlorothiazide.

4.6Fertility,pregnancyandlactation

AdalatLAiscontra-indicatedinwomencapableofchild-bearing.

ThesafetyofAdalatLAforuseinhumanpregnancyhasnotbeenestablished.Evaluationofexperimentalanimal

studieshasshownreproductivetoxicityconsistingofembryotoxicityandteratogeniceffectsatmaternallytoxicdoses.

AdalatLAiscontra-indicatedinnursingmothersasnifedipinemaybepresentinbreastmilk.

Insinglecasesofinvitrofertilisationcalciumantagonistslikenifedipinehavebeenassociatedwithreversible

biochemicalchangesinthespermatozoa’sheadsectionthatmayresultinimpairedspermfunction.Inthosemenwho

arerepeatedlyunsuccessfulinfatheringachildbyinvitrofertilisation,andwherenootherexplanationcanbefound,

calciumantagonistslikenifedipineshouldbeconsideredaspossiblecauses.

4.7Effectsonabilitytodriveandusemachines

Reactionstothedrug,whichvaryinintensityfromindividualtoindividual,mayimpairtheabilitytodriveorto

operatemachinery.Thisappliesparticularlyatthestartoftreatment,onchangingthemedicationandincombination

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4.8Undesirableeffects

Mostundesirableeffectsareconsequencesofthevasodilatoryeffectsofnifedipineandusuallyregressupon

withdrawaloftherapy.

Inallclinicalstudies(nifedipine,n=9566),thefollowingundesirableeffectswerecommonlyreported(>1%<10%

incidence):headache,palpitationsandvasodilatationwhichoccurmostfrequentlyintheearlystagesoftreatment,

lethargy,constipation,dizzinessandoedemaparticularlyperipheraloedemanotassociatedwithheartfailureorweight

gain.

Additionally,uncommonandrareundesirableeffectswerealsoreported:

Uncommon(>0/1%<1%)

Bodyasawhole: abdominalpain;chestpain;legpain,pain;malaise

Cardiovascular: hypotension;posturalhypotension;syncope;tachycardia

Digestive: diarrhoea;drymouth;dyspepsia;flatulence;nausea

Musculo-skeletal: legcramps

Nervous: insomnia;nervousness;paraesthesia;somnolence;vertigo

Respiratory: dyspnoea

Skin: pruritus;rash

Urogenital: nocturia;polyuria.

Rare(>0.01%<0.1%)

Bodyasawhole: allergicreaction;chestpainsubsternal;chills;facialoedema;fever;

hypersensitivity-typejaundice

Cardiovascular: cardiovasculardisorder

Digestive: anorexia;eructation;gastrointestinaldisorder;gingivitis;gingivalhyperplasia;

GGTincreased;liverfunctiontestabnormalities;vomiting

Musculo-skeletal: arthralgia;jointdisorder;myalgia

Nervous: hyperaesthesia;sleepdisorder,tremor;moodchanges

Respiratory: epistaxis

Skin: angioedema;maculopapular,pustularandvesiculobullousrash;sweating;urticaria

Specialsenses: abnormalvision;eyedisorder;eyepain

Urogenital: dysuria;impotence.

Aswithothersustainedreleasedihydropyridinesexacerbationofanginapectorismayoccurrarelyatthestartof

treatmentwithsustainedreleaseformulationsofnifedipine.Theoccurrenceofmyocardialinfarctionhasbeen

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Forspontaneousreports(n=2886)thefollowingundesirableeffectswerereportedveryrarelyworldwide(<0.01%):

anaphylacticreaction,bezoar,dysphagia,oesophagitis,gumdisorder,intestinalobstruction,intestinalulcer,jaundice,

increaseinALT,leucopenia,purpura,hyperglycaemia,weightloss,musclecramps,exfoliativedermatitis,

photosensitivedermatitisandblurredvision.Therehavealsobeenreportsofgynaecomastiainoldermenonlong-term

therapy,butthisusuallyregressesuponwithdrawaloftherapy.

4.9Overdose

Symptoms

Thefollowingsymptomsareobservedincasesofseverenifedipineintoxication:

Disturbancesofconsciousnesstothepointofcoma,adropinbloodpressure,tachycardiac/bradycardiacheartrythym

disturbances,hyperglycaemia,metabolicacidosis,hypoxia,cardiogenicshockwithpulmonaryoedema.

Treatment

Asfarastreatmentisconcerned,eliminationofnifedipineandtherestorationofstablecardiovascularconditionshave

priority.

Afteroralingestion,gastriclavageisindicated,ifnecessaryincombinationwithirrigationofthesmallintestine.

Eliminationmustbeascompleteaspossible,includingthesmallintestine,topreventtheotherwiseinevitable

subsequentabsorptionoftheactivesubstance.

Haemodialysisservesnopurpose,asnifedipineisnotdialyzable,butplasmapheresisisadvisable(highplasmaprotein

binding,relativelylowvolumeofdistribution).

Hypotensionasaresultofcardiogenicshockandarterialvasodilatationcanbetreatedwithcalcium(10–20mlofa

10%calciumgluconatesolutionadministeredintravenouslyover5-10minutes).Iftheeffectsareinadequate,the

treatmentcanbecontinued,withECGmonitoring.Ifaninsufficientincreaseinbloodpressureisachievedwith

calcium,vasoconstrictingsympathomimeticssuchasdopamineornoradrenalineshouldbeadministered.

Thedosageofthesedrugsshouldbedeterminedbythepatient’sresponse.

Bradycardiamaybetreatedsymptomaticallywithbeta-sympathomimeticsoratemporarycardiacpacemaker,as

required.

Additionalfluidsshouldbeadministeredwithcautiontoavoidcardiacoverload.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCcode:C08CA05

SelectiveCalciumchannelblocker(Dihydropyridinederivative)withmainlyvasculareffects.

Asaspecificandpotentcalciumantagonist,themainactionofnifedipineistorelaxarterialsmoothmuscle,bothinthe

coronaryandperipheralcirculation.TheAdalatLAtabletisformulatedtoachievecontrolleddeliveryofnifedipineina

releaseprofilesufficienttoenableonce-dailyadministrationtobeeffectiveinclinicaluse.

Inhypertension,themainactionofnifedipineistocauseperipheralvasodilatationandthusreduceperipheral

resistance.Nifedipineadministeredonce-dailyprovides24-hourcontrolofraisedbloodpressure.

Nifedipinecausesreductioninbloodpressuresuchthatthepercentageloweringisproportionaltoitsinitiallevel.In

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Inangina,AdalatLAreducesperipheralandcoronaryvascularresistance,leadingtoanincreaseincoronaryblood

flow,cardiacoutputandstrokevolume,whilstdecreasingafter-load.Additionally,nifedipinedilatessubmaximally

bothclearandatheroscleroticcoronaryarteries,thusprotectingtheheartagainstcoronaryarteryspasmandimproving

perfusiontotheischaemicmyocardium.NifedipinereducesthefrequencyofpainfulattacksandtheischaemicECG

changesirrespectiveoftherelativecontributionfromcoronaryarteryspasmoratherosclerosis.

Inmulti-national,randomised,double-blind,prospectivestudyinvolving6321hypertensivepatientswithatleastone

additionalriskfactorfollowedover3to4.8years,AdalatLA30and60(nifedipineGITS)wereshowntoreduce

cardiovascularandcerebrovasculareventstoacomparabledegreeasastandarddiureticcombination.

5.2Pharmacokineticproperties

Generalcharacteristics:

Orallyadministerednifedipineisalmostcompletelyabsorbedinthegastro-intestinaltract.Nifedipineundergoesfirst-

passmetabolismintheliver,givingasystemicavailabilityof45-68%followingoraladministration.Atsteady-state,

thebioavailabilityofAdalatLAtabletsrangesfrom68-86%relativetoAdalatcapsules.Administrationinthe

presenceoffoodslightlyalterstheearlyrateofabsorptionbutdoesnotinfluencetheextentofdrugavailability.

Nifedipineisalmostcompletelymetabolisedintheliver.Nifedipineiseliminatedintheformofitsmetabolites,

predominatelyviathekidneys,withapproximately5-15%beingexcretedviathebileinthefaeces.Non-metabolised

nifedipinecanbedetectedonlyintraces(below1.0%)intheurine.Nifedipineisapproximately95%boundtoplasma

protein.

TheAdalatLAtabletisformulatedtoreleasenifedipineinacontrolledwaytoenableonce-dailyadministration.

Thepharmacokineticprofileofthisformulationischaracterisedbylowpeak-troughfluctuation.0-24hourplasma

concentrationversustimeprofilesatsteady-stateareplateau-like,renderingtheAdalatLAtabletappropriateforonce-

a-dayadministration.

Characteristicsinpatients:

Therearenosignificantdifferencesinthepharmacokineticsofnifedipinebetweenhealthysubjectsandsubjectswith

renalimpairment.Therefore,dosageadjustmentisnotneededinthesepatients.

Inpatientswithhepaticimpairment,theeliminationhalf-lifeisdistinctlyprolongedandthetotalclearanceisreduced.

Owingtothedurationofactionoftheformulation,AdalatLAshouldnotbeadministeredinthesepatients.

5.3Preclinicalsafetydata

Followingacuteoralandintravenousadministrationofnifedipineinvariousanimalspecies,thefollowingLD

(mg/kg)valueswereobtained:

Mouse: Oral:454(401-572)*; i.v.:4.2(3.8-4.6)*

Rat: Oral:1022(950-1087)*; i.v.:15.5(13.7-17.5)*

Rabbit: Oral:250-500; i.v.:2-3

Cat: Oral:~100; i.v.:0.5-8

Dog: Oral:>250; i.v.:2-3

*95%confidenceinterval.

Insubacuteandsubchronictoxicitystudiesinratsanddogs,nifedipinewastoleratedwithoutdamageatdosesofupto

50mg/kg(rats)and100mg/kg(dogs)p.o.overperiodsofthirteenandfourweeks,respectively.Following

intravenousadministration,dogstoleratedupto0.1mg/kgnifedipineforsixdayswithoutdamage.Ratstolerateddaily

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Inchronictoxicitystudiesindogswithtreatmentlastinguptooneyear,nifedipinewastoleratedwithoutdamageat

dosesuptoandincluding100mg/kgp.o.Inrats,toxiceffectsoccurredatconcentrationsabove100ppminthefeed

(approximately5-7mg/kgbodyweight).

Inacarcinogenicitystudyinrats(twoyears),therewasnoevidenceofacarcinogeniceffectofnifedipine.

Instudiesinmice,ratsandrabbits,adosewhichwasmaternallytoxicinducedteratogeniceffectsinsomecasesand

embryotoxicity.

Inin-vitroandin-vivotests,nifedipinehasnotbeenassociatedwithmutagenicproperties.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

ExcipientspresentintheproductimportedfromTheNetherlands:

Polyethyleneoxide

Hypromellose

Magnesiumstearate

Sodiumchloride

Ironoxidered(E172)

Celluloseacetate

Macrogol

Hyprolose

Propyleneglycol

Titaniumdioxide(E171)

Printingink(shellac,ironoxideblack(E172))

ExcipientspresentintheproductimportedfromGreece:

Polyethyleneoxide

Hypromellose

Magnesiumstearate

Sodiumchloride

Ironoxidered(E172)

Celluloseacetate

Macrogol4000

Propyleneglycol

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

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6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

Blisterpackscontaining28tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA0465/012/005

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:14 th

December2001

Dateoflastrenewal:14 th

December2006

10DATEOFREVISIONOFTHETEXT

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